Molecular Mechanisms Linking Tobacco Smoke to DNA Damage and Carcinogenesis
DOI:
https://doi.org/10.54536/ajmsi.v4i2.6400Keywords:
Carcinogenesis, DNA Damage, MicroRNA, Oxidative Stress, Tobacco SmokeAbstract
Although tobacco smoke is a powerful environmental carcinogen, the molecular pathways through which its components cause DNA damage and cancer have not been completely defined. To elucidate mechanisms of tobacco smoke extract (TSE) induced genotoxicity, human bronchial epithelial and lung carcinoma cells were treated with TSE. Exposure to TSE resulted in dose-dependent elevation of reactive oxygen species and lipid peroxidation, which were followed by the attenuation of antioxidant defense. Comet assays and γ-H2AX foci formation showed a marked DNA strand break, and the key genes and proteins of DNA repair (OGG1, XRCC1, XPA, ERCC1) were under expressed compared to normal levels indicating lowering repair capability. Epigenetic analyses revealed an increase in overall DNA methylation and induction of tumor inhibitor genes by promoter hypermethylation (p16^INK4a, RASSF1A, MGMT) and oncomiR activation (miR-21 overexpression), coupled with a loss of expression of other anti-oncogenic miRs including miR-34a/miR-200c. The apoptotic pathway was also initiated as revealed by upregulation of p53 and an increased ratio of Bax to Bcl-2. Overall, these results expose a mechanistic cascade whereby chronic oxidative stress DNA damage, repair inhibition and epigenetic disruption cooperate to drive cancer development. The research highlights the importance of preventive measures, early biomarker detection and tailored antismoking intervention to reduce cancer risk from tobacco use.
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